The central objective of this proposal is to develop an understanding of the physical basis for protein-protein interactions. Several systems are to be studied, including the interaction of the apoptosis adaptor protein RAIDD with the prodomain of an ICH-1 protease; the putative N-terminal domains of the SV40 T antigen that interact with retinoblastoma protein and Hsc70; and the interaction of the T-cell surface proteins hCD2 and HCD58. In addition, an attempt will be made to convert miniproteins with a pre-defined scaffold structure into ligands of target proteins by random mutagenesis using phage display technologies. The principle structural method will be NMR spectroscopy and the thermodynamic properties of the various systems will be defined using isothermal titration calorimetry and surface plasmon resonances, as required. These studies are proposed to characterize protein-protein interactions and to develop an understanding of the underlying principles guiding the formation of specific protein-protein interfaces.